Obesity is one of the most prevalent diseases in Western society. The implications of this disorder of energy balance are broad and costly. Dietary and lifestyle changes are ineffective to produce meaningful, long- lasting weight reduction in the majority of the obese and overweight population, suggesting the urgent importance of finding effective pharmacological strategies to produce weight loss. One potential target for weight loss therapies is the glucagon-like peptide-1 (GLP-1) system. Drugs that activate GLP-1 receptors are FDA-approved to treat the impairments in glycemic control associated with type II diabetes mellitus, and these drugs have the additional effects of reducing food intake and body weight in humans and animal models. Understanding more about the mechanisms by which GLP-1 receptor activation produces sustained body weight loss and inhibition of food intake, especially of palatable foods, may provide insight into effective obesit treatments. The main goal of this proposal is to train the fellowship applicant in a variety of in vivo, in vitro, and ex vivo techniques to probe the role of caudal brainstem GLP-1 receptor-expressing neurons in the integration of energy status signals and the long-term reductions in food intake and body weight produced by GLP-1 receptor activation. Specific Aim I tests the hypothesis that cAMP response element binding protein (CREB), an intracellular mediator of gene expression, is required for the sustained energy balance effects of GLP-1 receptor activation. Adeno-associated virally (AAV)-mediated knockdown of CREB in the medial nucleus of the solitary tract (mNTS), a key caudal brainstem structure for both GLP-1 signaling and the broader integration of energy status signals, will be used to determine the requirement of mNTS CREB for the effects of GLP-1 receptor signaling on behavioral and physiological endpoints related to energy balance and glycemic control. Additionally, a cell culture model will be utilized to probe the intracellular signaling pathways recruited by GLP-1 receptor activation to determine which are necessary for CREB activation. The experiments proposed in Specific Aim II test the effects of chronic selective alterations of hindbrain GLP-1 receptor signaling on energy balance and glycemic phenotypes, as well as gene expression and changes in GLP-1 receptor signal transduction. Experiments in this proposal use a unique combination of in vivo, in vitro, and ex vivo techniques to investigate the research questions described.